Tuberculosis (TB) is an infectious disease that typically attacks the lungs, but is capable of attacking most parts of the body. Tuberculosis is caused by Mycobacterium tuberculosis, and is spread from person to person through the air. When individuals infected with TB cough, laugh, sneeze, sing, or talk, TB bacteria can be spread. If a second person inhales TB bacteria, a possibility exists that the second person also will become infected with tuberculosis. However, repeated contact typically is required for infection.
TB is a primary public health threat, and is an increasing worldwide problem, especially in Africa. TB is the single leading cause of death from an infectious disease worldwide, and it is estimated that, worldwide, one third of the population is infected with latent TB, over 150 million people will contract active TB, and about 36 million people will die over the next 20 years unless TB control is improved. Medical experts estimate that about 10 million Americans are infected with TB bacteria, and about 10 percent of these individuals will develop active TB in their lifetime. Furthermore, HIV and TB form a lethal combination, with each condition speeding the progress of the other condition.
Except for very young children, few individuals become sick immediately after tuberculosis bacteria enter the body. Many tuberculosis bacteria that enter the lungs are immediately killed by the body's immune system. TB bacteria that survive are captured inside white blood cells called macrophages. The captured bacteria can remain alive inside these cells in a dormant state for many years (latent TB). In 90 to 95% of cases, the TB bacteria cause no further problems. But in about 5 to 10% of infected people, the TB bacteria begin to multiply (active TB). It is in this active TB phase that an infected person actually becomes sick and can spread the disease.
Typically, activation of latent TB bacteria occurs within the first two years of infection, but activation may not occur for a very long time. The mechanism by which dormant bacteria becomes active is not precisely known, but activation often occurs when the immune system becomes impaired, for example, from advanced age, the use of corticosteroids, or HIV infection. Like many infectious diseases, tuberculosis spreads more quickly and is much more dangerous in individuals having a weakened immune system. For such individuals, including the very young, the very old, and those who are also infected with HIV, tuberculosis can be life threatening.
Presently-used drugs to treat TB were developed more than 40 years ago. Treatments using these drugs are very long and require an excessive number of doses, e.g., up to eight pills a day for longer than six months. The drug isoniazid is an effective anti-TB drug. Isoniazid (termed “INH”) is administered daily for 6 to 9 months. Shorter latent TB treatments use rifampin plus pyrazinamide daily for 2 months, or rifampin alone daily for 4 months. Such burdensome treatments increase patient noncompliance and can lead to an increase in multidrug-resistant tuberculosis (MDR TB). In addition, the presently-used drugs typically do not target latent, nonproliferating TB bacteria.
An individual infected with TB, but not suffering from TB disease, i.e., has latent TB, can be administered preventive therapy, which kills bacteria in order to prevent a case of active TB. An individual with a positive tuberculin skin test who becomes infected with HIV has a high risk of developing an active TB infection. Similarly, an individual who takes corticosteroids has a greatly increased risk of activating latent tuberculosis. Such individuals need a treatment for latent tuberculosis. An important aspect of TB prevention, therefore, is treating individuals diagnosed with latent TB.
If an individual has active TB, the individual typically is administered a combination of several drugs. It is very important, however, that the individual continue a correct treatment regimen for the full length of the treatment. If the drugs are taken incorrectly, or treatment is stopped, the individual can suffer a relapse and will be able to infect others with TB.
When an individual becomes sick with TB a second time, the TB infection may be more difficult to treat because the TB bacteria have become drug resistant, i.e., TB bacteria in the body are unaffected by some drugs used to treat TB. In particular, some TB bacteria become resistant to the effects of various anti-TB drugs, and these multidrug resistant TB bacteria then can cause MDR TB disease. MDR TB is a very dangerous form of tuberculosis, and like regular TB, MDR TB can be spread to other individuals.
To help avoid drug resistance in the treatment of TB, a four-drug regimen, i.e., isoniazid, rifampin, pyrazinamide, and streptomycin, is administered to TB patients. Aminoglycosides, such as streptomycin, are important anti-TB agents, but their utility is restricted by the requirement of parenteral administration, which is inconvenient and leads to poor patient compliance. It is theorized that poor patient compliance also can lead to the development of drug resistance, and it appears that the frequency of streptomycin resistance among anti-TB drugs is surpassed only by isoniazid.
In view of the above, an urgent need exists for new, effective anti-TB agents that are useful in a treatment regimen for both active and latent TB, and that effectively treat TB caused by multidrug resistant (MDR) strains of bacteria. Therefore, it would be advantageous to provide compounds and compositions for administration to an individual in the treatment of TB, and particularly latent TB. As set forth in detail hereafter, the present invention is directed to the use of 2-nitroimidazolyl-alkylaminoquinolines, and pharmaceutical compositions containing the same, for use in methods of treating tuberculosis, and particularly latent tuberculosis.
Compounds termed nitroimidazopyrans (NAPs) have been reported as having activity against known forms of TB (Stover et al., Nature, 405, 962-966, (2000)). One particular NAP is termed PA-824, having a structure
PA-824 is specific against M. tuberculosis. The NAPs perform differently from current anti-TB drugs because they are activated by reduction, rather than oxidation.
Another compound reported as being useful against latent TB bacteria is metronidazole (Edwards, Antimicrob. Chemother., 5, 499-502 (1999)) having a structure
Additional compounds useful in the treatment of latent TB would be an important advance in the art.